131I-Tositumomab Radioimmunotherapy: Initial Tumor Dose–Response Results Using 3-Dimensional Dosimetry Including Radiobiologic Modeling

There has been recent interest in developing dosimetry-based patient-specific treatment planning to optimize therapy with internal emitters as is routine in external-beam therapy. Because of the inherent heterogeneity of radiopharmaceutical distribution in tumor and normal organs, the preferred methodology for absorbed dose estimation is imaging-based 3-dimensional (3D) calculation (1). The recent advances in hybrid imaging and computational power have made such calculations possible in a research environment and a realistic clinical goal for the future. At present, the common approach for 131I anti-CD20 radioimmunotherapy of lymphoma is to deliver 65–75 cGy to the whole body based on estimates from a tracer study. Although this conservative approach has produced promising results (2,3), there is much room for improving efficacy by tailoring the treatment on a patient-by-patient basis to deliver the therapeutic absorbed dose to the tumor while avoiding critical organ toxicity. Apart from treatment planning, tumor-absorbed dose estimates from a tracer study can potentially be used for improved clinical management by timely initiation of alternative treatment. To make advances toward tumor dosimetry–based radionuclide therapy, robust tumor dose–response correlations must be established. Studies on tumor dosimetry in radioimmunotherapy of lymphoma are limited and have not established strong dose–response correlations for either of the 2 Food and Drug Administration–approved radiopharmaceuticals, 90Y-ibritumomab or 131I-tositumomab (4–7). In these past studies, the mean absorbed dose to the tumor was the only dose measure that was calculated, except in the study by Sgouros et al., in which correlations were also investigated with minimum absorbed dose, maximum absorbed dose, and a uniformity index. Although the equivalent uniform dose (EUD) model has been proposed for assessing the biologic effect of a nonuniform tumor-absorbed dose distribution (8), it has not been used in past studies evaluating dose–response correlations. Past tumor dosimetry studies have also relied on planar imaging methods or methods combining SPECT at a single time point with planar imaging at multiple time points to determine pharmacokinetics. The superiority of SPECT over planar methods for activity quantification is well established. Here, we present tumor dosimetry results from a fully 3D approach coupling hybrid SPECT/CT at multiple time points with Monte Carlo radiation transport–based voxel-by-voxel absorbed dose calculation. Past radioimmunotherapy studies have shown dramatic regression of malignant lymphomas within days of the therapeutic administration (9–11). In the present study, the anatomic CT information from multiple time points allowed us to incorporate tumor regression and deformation into the calculation to estimate spatial absorbed dose distributions at the voxel level. In addition, EUD was calculated to assess the biologic effects of the nonuniform absorbed dose, including the effects of the cold antibody administered with the 131I-labeled antibody and the effects of cell proliferation (12). Tumor dose–response correlations were investigated using mean absorbed dose and EUD as well as other measures from dose-volume histogram analysis.